Multisubstituted Allenes Research Articles

Highly efficient synthesis of di-substituted allenes via copper-catalyzed SN2′- substitution reaction of organotitanium reagents with propargyl bromides

A simple and mild catalytic SN2′-type displacement of propargyl halides with organotitanium reagents is reported. The SN2′-type displacement of propargyl bromides with organotitanium reagents mediated by CuI (2 mol%)/MePPh2(4 mol%) in dichloro methane afforded multi-substituted allenes in good yields (up to 95 %) at 40 °C for 5 h. The aryls bearing electron-donating or electron-withdrawing groups in aryltitanium reagents gave multi-substituted allenes in good yields. In addition, the di-substituted allenes bearing a naphthyl group was obtained in 54–99 % selectivities with isolated yields of 43–83 %. The process was simple and easily performed, and it provides an efficient method for the synthesis of di-substituted allene derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Photoexcited Palladium-Catalyzed Deracemization of Allenes.

The different enantiomers of specific chiral molecules frequently exhibit disparate biological, physiological, or pharmacological properties. Therefore, the efficient synthesis of single enantiomers is of particular importance not only to the pharmaceutical sector but also to other industrial sectors, such as agrochemical and fine chemical industries. Deracemization, a process during which a racemic mixture is converted into a nonracemic product with 100% atom economy and theoretical yield, is the most straightforward method to access enantioenriched molecules but a challenging task due to a decrease in entropy and microscopic reversibility. Axially chiral allenes bear a distinctive structure of two orthogonal cumulative π-systems and are acknowledged as synthetically versatile synthons in organic synthesis. The selective creation of axially chiral allenes with high optical purity under mild reaction conditions has always been a very popular and hot topic in organic synthesis but remains challenging. Herein, a photoexcited palladium-catalyzed deracemization of nonprefunctionalized disubstituted allenes is disclosed. This method provides an efficient and economical strategy to accommodate a broad scope of allenes with good enantioselectivities and yields (53 examples, up to 96% yield and 95% ee). The use of a suitable chiral palladium complex with visible light irradiation is an essential factor in achieving this transformation. A metal-to-ligand charge transfer mechanism was proposed based on control experiments and density functional theory calculations. Quantum mechanical studies implicate dual modes of asymmetric induction behind our new protocol: (1) sterically controlled stereoselective binding of one allene enantiomer under the ground-state and (2) facile, noncovalent interaction-driven excited-state isomerization toward the opposite enantiomer. The success of this newly established photochemical deracemization strategy should provide inspiration for expansion to other multisubstituted allenes and will open up a new mode for enantioselective excited-state palladium catalysis.

Visible-Light-Induced Regioselective Radical-Polar Crossover 1,4-Hydrophosphinylation of 1,3-Enynes: Access to Trisubstituted Allenes Bearing a Phosphine Oxide Group.

The radical 1,4-functionalizations of 1,3-enynes have emerged as a powerful strategy for the synthesis of multisubstituted allenes. However, the phosphorus-centered radical-initiated transformations remain largely elusive. Herein, visible-light photoredox catalytic regioselective radical hydrophosphinylation of 1,3-enynes with diaryl phosphine oxides as phosphinoyl radical precursors has been realized. This protocol features mild conditions, a wide substrate scope, and good functional group tolerance, producing a diverse range of phosphinoyl-substituted allenes in moderate to good yields with high atom economy. Detailed mechanistic experiments revealed a radical-polar crossover process in the reaction.

Synthesis of Multisubstituted Allenes by Palladium-Catalyzed Carboetherification of β,γ-Unsaturated Ketoximes with Propargylic Acetates.

A highly efficient Pd-catalyzed carboetherification reaction of β,γ-unsaturated ketoximes with propargylic acetates is demonstrated. This method provides a practical protocol for accessing the incorporation of an allene moiety into 3,5-disubstituted and 3,5,5-trisubstituted isoxazolines. The salient features of this transformation include a broad substrate scope, good functional group tolerance, an easy scale-up, versatile transformations, and applications in the late-stage modification of drugs.

Photoredox Catalyzed Sulfonylation of Multisubstituted Allenes with Ru(bpy)3Cl2 or Rhodamine B

A highly regio- and stereoselective sulfonylation of allenes was developed that provided direct access to α, β-substituted unsaturated sulfone. By means of visible-light photoredox catalysis, the free radicals produced by p-toluenesulfonic acid reacted with multisubstituted allenes to obtain Markovnikov-type vinyl sulfones with Ru(bpy)3Cl2 or Rhodamine B as photocatalyst. The yield of this reaction could reach up to 91%. A series of unsaturated sulfones would be used for further transformation to some valuable compounds.

Synthesis of Multisubstituted Allenes via Nickel-Catalyzed Cross-Electrophile Coupling

Synthesis of Multisubstituted Allenes via Nickel-Catalyzed Cross-Electrophile Coupling

Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis.

We disclose herein the first example of merging photoredox catalysis and copper catalysis for radical 1,4-carbocyanations of 1,3-enynes. Alkyl N-hydroxyphthalimide esters are utilized as radical precursors, and the reported mild and redox-neutral protocol has broad substrate scope and remarkable functional group tolerance. This strategy allows for the synthesis of diverse multi-substituted allenes with high chemo- and regio-selectivities, also permitting late stage allenylation of natural products and drug molecules.

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd‐Catalyzed 1,4‐Arylboration of 1,3‐Enynes

AbstractA cooperative Cu/Pd‐catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl2(dppf) complexes as catalysts, the 1,4‐arylboration of 1,3‐enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2‐substituted 1,3‐enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate‐limiting step of this transformation.

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-Enynes.

A cooperative Cu/Pd-catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl2 (dppf) complexes as catalysts, the 1,4-arylboration of 1,3-enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2-substituted 1,3-enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate-limiting step of this transformation.

Nickel‐Catalyzed Carbofluoroalkylation of 1,3‐Enynes to Access Structurally Diverse Fluoroalkylated Allenes

AbstractA nickel‐catalyzed 1,4‐carbofluoroalkylation of 1,3‐enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional‐group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4‐difunctionalization of 1,3‐enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.

Nickel-Catalyzed Carbofluoroalkylation of 1,3-Enynes to Access Structurally Diverse Fluoroalkylated Allenes.

A nickel-catalyzed 1,4-carbofluoroalkylation of 1,3-enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional-group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4-difunctionalization of 1,3-enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.

Cu-catalyzed regio- and stereoselective sulfonylation of multi-substituted allenes

Regio- and stereoselective sulfonylation of allenes under Cu catalysis is described. Allenyl sp carbons exclusively react with TsCN to give the corresponding alkenyl sulfones. The reaction is initiated by addition of tosyl radical to form benzyl radical intermediates, which determines the reaction pathway. The structure of the products is highly dependent on the substituents on allenes.

Copper-Catalyzed Radical 1,4-Difunctionalization of 1,3-Enynes with Alkyl Diacyl Peroxides and N-Fluorobenzenesulfonimide.

Many reactions involving allenyl ion species have been studied, but reactions involving allenyl radicals are less well understood, perhaps because of the inconvenience associated with the generation of short-lived allenyl radicals. We describe here a versatile method for the generation of allenyl radicals and their previously unreported applications in the intermolecular 1,4-carbocyanation and 1,4-sulfimidocyanation of 1,3-enynes. With the assistance of the trifunctional reagents, alkyl diacyl peroxides or N-fluorobenzenesulfonimide, a range of synthetically challenging multisubstituted allenes can be prepared with high regioselectivity. These multisubstituted allenes can be easily transformed into synthetically useful structures such as fluorinated vinyl cyanides, lactones, functionalized allenyl amides, 1-aminonaphthalenes, and pyridin-2(1 H)-ones, and several novel transformations are reported. The results of radical scavenger and radical clock experiments are consistent with the proposed allenyl radical pathway. Density functional theory (DFT) and IR spectroscopy studies suggest the formation of an isocyanocopper(II) species in the ligand exchange step. On the basis of the results of IR, DFT, and diastereoselectivity studies, an isocyanocopper(II)/copper(I) catalytic cycle is proposed, which differs from the previously considered Cu(III) mechanism in cyanation reactions.

Palladium-catalyzed, ligand-free SN2’ substitution reactions of organoaluminum with propargyl acetates for the synthesis of multi-substituted allenes

We describe a convenient method for the synthesis of multi-substituted allenes from SN2′ substitution reactions organoaluminum with propargyl acetates: The SN2′ substitution reaction of organoaluminum (0.4 mmol) with propargyl acetates (0.5 mmol) mediated by PdCl2(dppf) (1 mol%) at 60 °C in THF without ligand could produce multi-substituted allenes in moderate to good yields (up to 98%) and high selectivities (up to 99%). Their structures have been determined by HRMS and 1H (13C)NMR data.

Synthesis of multi-substituted allenes from organoalane reagents and propargyl esters by using a nickel catalyst.

A highly efficient and simple route for the synthesis of multi-substituted allenes has been developed by a nickel catalyzed SN2' substitution reaction of propargyl esters with organic aluminium reagents under mild conditions, which gave the corresponding multi-substituted allenes in good to excellent yields (up to 92%) and high selectivities (up to 99%) at 60 °C for 6 h in THF. Aryls bearing electron-donating or electron-withdrawing groups in propargyl esters gave products in good yields. In addition, the multi-substituted allenes bearing a thienyl or a pyridyl group were obtained in 95-97% selectivities with isolated yields of 72-83%. Furthermore, the SN2' substitution reaction worked efficiently with propargyl carbonate compounds as well. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Highly Efficient Synthesis of Multi-Substituted Allenes from Propargyl­ Acetates and Organoaluminum Reagents Mediated by Palladium

A simple and mild catalytic SN2′ substitution reaction of propargyl acetates with organoaluminum reagents is reported. The SN2′ substitution reaction of propargyl acetates with organoaluminum reagents mediated by Pd(PhP3)2Cl2 (1 mol%)/PPh3 (2 mol%)/K2CO3 in tetrahydrofuran at 60 °C for 3–4 hours afforded the corresponding multi-substituted allenes in good yields (up to 94%) with high selectivities (up to 99%). The process was simple and easily performed, which offers an efficient method to synthesize the multi-substituted allene derivatives.

Synthesis of Multisubstituted Allenes, Furans, and Pyrroles via Tandem Palladium-Catalyzed Substitution and Cycloisomerization.

A palladium-catalyzed propargyl substitution reaction of propargyl acetates with indium organothiolates is developed for the synthesis of multisubstituted allenyl sulfides. This procedure can be applied to the synthesis of multisubstituted furans and pyrroles via tandem palladium-catalyzed propargyl substitution and cycloisomerization reaction in one pot.

Synthesis of Multisubstituted Allenes via Palladium-Catalyzed Cross-Coupling Reaction of Propargyl Acetates with an Organoaluminum Reagent

We describe a convenient method for the synthesis of multisubstituted allenes from cross-coupling of propargyl acetates with ­organoaluminum reagent: The reaction of propargyl acetates with 1.2 equivalents of organoaluminum reagent mediated by Pd(PPh₃)₂Cl₂ (1 mol%)/Ph₃P (2 mol%) and K₂CO₃ in THF may produce tri- or tetrasubstituted allenes in good to excellent yields (83–94%) and high regio­selectivities (up to 99%) at 60 °C in 3–4 hours.

Catalytic transient leaving group for atom-economic synthesis of allenes from 2-alkynols.

An atom economic approach from readily available propargylic alcohols to allenes, the first carboxylation of propargylic alcohols, has been established. Through the cooperative binary catalysis of Pd and a phosphoric acid, the reaction afforded multi-substituted allenoates with a broad scope tolerating useful functional groups. The synthetic potential of the obtained products has been demonstrated.

ChemInform Abstract: General Approach to Allenes Through Copper‐Catalyzed γ‐Selective and Stereospecific Coupling Between Propargylic Phosphates and Alkylboranes.

AbstractCopper‐catalyzed γ‐selective coupling between propargylic phosphates (II) and alkyl boron compounds (V), in some cases prepared in situ by hydroboration of alkenes (I), affords multisubstituted allenes (III) and (VIII) with various functional groups.